Genetic Modifiers of Cognitive Function: Novel Genetic Associations with Memory, Executive Function, and Attention in the Long Life Family Study

Cognitive performance is central to health and quality of life. Studying the factors that sustain performance may offer insights into maintaining cognitive function into advanced ages and may inform strategies to promote healthy cognitive aging. To identify single nucleotide polymorphisms (SNPs) underlying cognitive function, we performed genome-wide association studies (GWAS) of nine neuropsychological test scores capturing performance in three cognitive domains in 2,455 participants of the Long Life Family Study (LLFS). We identified 12 variants in seven tests and three domains that reached genome-wide significance (p < 5x10-). Three rare (minor allele frequency, European population MAF<0.01) protective, intronic variants, rs190287985 (CCSER1), rs75730801 (FHOD3), and rs552842447 (LINC00508), were uniquely associated with semantic fluency, phonemic fluency and number span forward, respectively. Two rare deleterious variants, rs556333682 and rs188304645, were associated with performance on the Hopkins Verbal Learning Test-Revised (HVLT-R) learning trials and lie in ischemia-related genes SH3TC1 and RPH3A. Another variant, rs180691759, associated with HVLT-R delayed recall, was proximal to RSPO3 and linked to decreased ECHDC1 expression, implicating ischemic and unexplained Ethylmalonic acid (EMA) pathways. We compared the results with GWASs of a general cognitive factor (GCF) and reaction time (RT) in the UK Biobank and meta-analysis results of the UK Biobank, CHARGE and COGENT by Davies et al. We found that rs535509651 associates with HVLT-R delayed recall in the LLFS and nominally associates (p<0.05) with GCF, and that rs10424537 associates with Immediate Logical Memory in the LLFS and nominally associates with RT. Furthermore, we identified 5 genome-wide significant loci in Davies et al. that reached loci adjusted significance in the LLFS (GCF p<0.05/128 and RT p<0.05/39). Each locus was associated with a single cognitive domain in the LLFS. We annotated the genome-wide significant results with quantitative trait loci (QTL) analyses of whole blood transcriptomic, serum metabolomic data, and gene set enrichment analyses (GSEA) using all nominally significant transcripts (p < 0.05/12). QTL analyses discovered 1 SNP-transcript (ECHDC1, p < 3 x 10-6), no SNP-lipid (p < 2 x 10-4), and no SNP-polar metabolite (p < 2 x 10-4) associations. Gene set enrichment analyses identified three pathways at FDR < 0.05. Our findings provide insight into the domain-specific genetic architecture of cognitive function.